Non-alcoholic fatty liver disease and cardiovascular risk

Table 1 Recent epidemiological studies evaluating cardiovascular risk in non-alcoholic fatty liver disease

Ref.	Study characteristics	Years of follow-up	Diagnosis of NAFLD	Study outcomes	Main findings
Ekstedt et al[30] (2015)	Retrospective cohort study n = 229 Swedish patients with NAFLD and elevated liver enzymes (49% NASH); mean age 49 yr, 66% men	26.4 (mean)	Histology	n = 96 total deaths, 41 CVD related deaths	Increased rates of all-cause, liver-related and CVD mortality with NAFLD compared with general control population. Fibrosis stage on histology significantly predicted the risk of all-cause, liver-related and CVD mortality
Ekstedt et al[31] (2006)	Cohort study 129 consecutively enrolled patients diagnosed with biopsy-proven NAFLD were reevaluated. Survival and causes of death were compared with a matched reference population. Living NAFLD patients were offered repeat liver biopsy and clinical and biochemical investigation	13.7 (mean)	Histology	Mortality was not increased in patients with steatosis. Survival of patients with nonalcoholic steatohepatitis (NASH) was reduced. These subjects more often died from cardiovascular and liver-related causes. At follow-up, 69 of 88 patients had diabetes or impaired glucose tolerance. Progression of liver fibrosis occurred in 41%. These subjects more often had a weight gain exceeding 5 kg, they were more insulin resistant, and they exhibited more pronounced hepatic fatty infiltration at follow-up	Increased total mortality which was primarily CV related (only in NASH patients but not in simple steatosis) compared with matched reference population
Soderberg et al[11] (2010)	Retrospective cohort study 256 subjects (61% men, mean age of 45 ± 12 yr) This study was undertaken to determine the frequency of NAFLD in a cohort of subjects who underwent liver biopsy from 1980 to 1984 because of elevated liver enzymes, and to assess mortality among subjects with NAFLD in comparison with the general Swedish population. Liver biopsies were blindly scored for NAFLD and NASH	24 yr (mean)	Histology	During the follow-up period, 113 (44%) of the total population and 47 (40%) of the 118 subjects diagnosed with NAFLD died. Of the 113 deaths, 37 were of cardiovascular disease and 16 of liver diseases. NAFLD exhibited a 69% increased mortality, subjects with bland steatosis, a 55% increase, and subjects with NASH, 86%	Increased total mortality in NAFLD was predominantly CV related, compared with matched reference population
Pickhardt et al[32] (2014)	Retrospective cohort study United States adults undergoing abdominal CT selected among 4412 consecutive adults scanned with CT for clinical reasons over a 12-mo period: 282 NAFLD patients and 786 non-steatotic controls after exclusion of those with known liver diseases or < 1 yr of follow-up; mean 51 yr, 46% men	7.5 (mean)	Unenhanced CT	Non-fatal CVD events (myocardial infarction, stroke, TIA or coronary bypass or stent); n = 73 CVD events	NAFLD was not independently associated with non-fatal CVD events
Zeb et al[12] (2016)	Prospective cohort study n = 4119 United States participants aged 45-84 yr (mean 62 yr, 45% men) who were free of CVD and known liver diseases at baseline	7.6 (mean)	Unenhanced CT	All-cause mortality and no-fatal CVD events (myocardial infarction, resuscitated cardiac arrest, angina, or coronary revascularization procedures), n = 253 deaths and 209 non-fatal CVD events	NAFLD was independently associated with a composite endpoint inclusive of all-cause death and non-fatal CVD events
Kim et al[33] (2013)	Population-based cohort n = 11154 Unites States adults; mean age 43 yr, 48% men	14.5 (median)	Ultrasound	All-cause and CVD mortality n = 1795 total deaths (673 CVD deaths)	NAFLD was not associated with increased all-cause and CVD mortality in the whole cohort however NAFLD with advanced fibrosis (defined by the NAFLD fibrosis score) was independently associated with increased all-cause and CVD mortality
Emre et al[34] (2015)	Retrospective cohort study n = 186 Turkish, non-diabetic patients undergoing PCI for ST-elevation MI; patients with known liver disease were excluded; mean age 58 yr, 78% men	In-hospital cardiac events	Ultrasound	In-hospital CVD events (MI, acute heart failure, cardiac arrest), n = 32 CVD events and n = 8 CVD deaths	Moderate-severe NAFLD was independently associated with increased in-hospital CVD events but not with increased CVD death

NAFLD: Non-alcoholic fatty liver disease; CT: Computed tomography; CAC: Coronary artery calcification; CIMT: Carotid intima-media thickness; CP: Carotid plaque; DM: Diabetes mellitus; NASH: Nonalcoholic steatohepatitis.

Table 2 Studies evaluating coronary artery disease and carotid disease in non-alcoholic fatty liver disease

Ref.	Study characteristics	Modality to assess CV risk	Diagnosis of NAFLD Ultrasound	Main findings
Sinn et al[16] (2016)	Retrospective cohort study - 8020 men (average age, 49.2 yr) without carotid atherosclerosis at baseline and with proven NAFLD	CIMT on carotid ultrasound		NAFLD was associated with an increased risk of subclinical carotid atherosclerosis development. This association was explained by metabolic factors that could be potential mediators of the effect of NAFLD. Markers of liver fibrosis also were associated with subclinical carotid atherosclerosis development
Pais et al[35] (2016)	Longitudinal cohort study - 1871 subjects (mean age 53 yr; 65% males). Half of cohort had steatosis while half did not	CIMT on carotid ultrasound	Fatty Liver Index	Steatosis occurred in 12% and CP in 23% of patients. C-IMT increased in patients with steatosis occurrence whereas it did not change in those that stayed free of steatosis. Steatosis at baseline predicted CP occurrence independent of age, sex, type-2 diabetes, tobacco use, hsCRP, hypertension and C-IMT
Park et al[36] (2016)	Longitudinal cohort study - 1732 subjects underwent serial CAC evaluation. Half the cohort had NAFLD and half did not	Calcium scoring CT to assess CAC	Ultrasound	More subjects with NAFLD than without showed CAC development or progression. In subjects without calcification at baseline, NAFLD significantly affected the development of calcification after adjusting for traditional metabolic risk factors. The severity of NAFLD was dose-dependently associated with the development of CAC
Kim et al[15] (2012)	Retrospective chart review- 4 023 subjects (mean age, 56.9 ± 9.4 yr; 60.7% males) without known liver disease or a history of ischemic heart disease	Calcium scoring CT to assess CAC	Ultrasound	Patients with NAFLD are at increased risk for coronary atherosclerosis independent of classical coronary risk factors, including visceral adiposity. These data suggest that NAFLD might be an independent risk factor for coronary artery disease
Fracanzani et al[20] (2016)	Longitudinal cohort study - 125 NAFLD patients and 250 age and gender matched Controls at baseline and 10 yr later were followed. Incidence of cardiovascular and cerebral events was recorded	CIMT on carotid ultrasound	Ultrasound	Major cardiovascular events were observed in 19% of NAFLD patients, with an estimated cumulative risk significantly higher in NAFLD than in Controls. Presence of plaques and of steatosis were the strongest predictors for cardiovascular events. Grade of steatosis, ALT and GGT levels were higher in NAFLD patients who developed cardiovascular events. CIMT value after 10 years was significantly higher in NAFLD than in Controls. NAFLD should be included among risk factors for cardiovascular damage and underline the utility to evaluate, once it is diagnosed, the presence of atherosclerotic lesions
Nahandi et al[17] (2014)	Case control study - 151 patients in three groups: group I including 49 patients with NAFLD and DM; group II including 50 non-diabetic NAFLD patients; and the control including 52 normal subjects as group III	CIMT on carotid ultrasound	Ultrasound	There is a significant association between the presence of NAFLD and atherosclerosis, but this association was independent of DM. The grade of NAFLD and elevated liver function tests had no effect on severity of atherosclerosis

NAFLD: Non-alcoholic fatty liver disease; CT: Computed tomography; CAC: Coronary artery calcification; CIMT: Carotid intima-media thickness; CP: Carotid plaque; DM: Diabetes mellitus.